Inhibition of NF-κB Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

被引：479

作者：

Shembade, Noula ^{[1
]}

Ma, Averil ^{[2
]}

Harhaj, Edward W. ^{[1
]}

机构：

[1] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

来源：

SCIENCE | 2010年 / 327卷 / 5969期

关键词：

CONJUGATING ENZYME; ACTIVATION; UBC13; RESPONSES; REQUIRES; SUSCEPTIBILITY; TERMINATION; TNFAIP3; REGION;

D O I：

10.1126/science.1182364

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A20 negatively regulates inflammation by inhibiting the nuclear factor kappa B (NF-kappa B) transcription factor in the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-kappa B signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest a mechanism of A20 action in the inhibition of inflammatory signaling pathways.

引用

页码：1135 / 1139

页数：5

共 24 条

[1] cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination [J].

Bertrand, Mathieu J. M. ;

Milutinovic, Snezana ;

Dickson, Kathleen M. ;

Ho, Wai Chi ;

Boudreault, Alain ;

Durkin, Jon ;

Gillard, John W. ;

Jaquith, James B. ;

Morris, Stephen J. ;

Barker, Philip A. .

MOLECULAR CELL, 2008, 30 (06) :689-700

[2] The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses [J].

Boone, DL ;

Turer, EE ;

Lee, EG ;

Ahmad, RC ;

Wheeler, MT ;

Tsui, C ;

Hurley, P ;

Chien, M ;

Chai, S ;

Hitotsumatsu, O ;

McNally, E ;

Pickart, C ;

Ma, A .

NATURE IMMUNOLOGY, 2004, 5 (10) :1052-1060

[3] Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma [J].

Compagno, Mara ;

Lim, Wei Keat ;

Grunn, Adina ;

Nandula, Subhadra V. ;

Brahmachary, Manisha ;

Shen, Qiong ;

Bertoni, Francesco ;

Ponzoni, Maurilio ;

Scandurra, Marta ;

Califano, Andrea ;

Bhagat, Govind ;

Chadburn, Amy ;

Dalla-Favera, Riccardo ;

Pasqualucci, Laura .

NATURE, 2009, 459 (7247) :717-U124

[4] Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-κB activation [J].

Conze, Dietrich B. ;

Wu, Chuan-Jin ;

Thomas, James A. ;

Landstrom, Allison ;

Ashwell, Jonathan D. .

MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (10) :3538-3547

[5] A20: Central Gatekeeper in Inflammation and Immunity [J].

Coornaert, Beatrice ;

Carpentier, Isabelle ;

Beyaert, Rudi .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (13) :8217-8221

[6] Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain [J].

Deng, L ;

Wang, C ;

Spencer, E ;

Yang, LY ;

Braun, A ;

You, JX ;

Slaughter, C ;

Pickart, C ;

Chen, ZJ .

CELL, 2000, 103 (02) :351-361

[7] Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-κB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility [J].

Dieguez-Gonzalez, Rebeca ;

Calaza, Manuel ;

Perez-Pampin, Eva ;

Balsa, Alejandro ;

Blanco, Francisco J. ;

Canete, Juan D. ;

Caliz, Rafael ;

Carreno, Luis ;

de la Serna, Arturo R. ;

Fernandez-Gutierrez, Benjamin ;

Maria Ortiz, Ana ;

Herrero-Beaumont, Gabriel ;

Pablos, Jose L. ;

Narvaez, Javier ;

Navarro, Federico ;

Marenco, Jose L. ;

Gomez-Reino, Juan J. ;

Gonzalez, Antonio .

ARTHRITIS RESEARCH & THERAPY, 2009, 11 (02)

[8] Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses [J].

Fukushima, Toru ;

Matsuzawa, Shu-ichi ;

Kress, Christina L. ;

Bruey, Jean Marie ;

Krajewska, Maryla ;

Lefebvre, Sophie ;

Zapata, Juan M. ;

Ronai, Ze'ev ;

Reed, John C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (15) :6371-6376

[9] Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus [J].

Fung, E. Y. M. G. ;

Smyth, D. J. ;

Howson, J. M. M. ;

Cooper, J. D. ;

Walker, N. M. ;

Stevens, H. ;

Wicker, L. S. ;

Todd, J. A. .

GENES AND IMMUNITY, 2009, 10 (02) :188-191

[10] Frequent inactivation of A20 in B-cell lymphomas [J].

Kato, Motohiro ;

Sanada, Masashi ;

Kato, Itaru ;

Sato, Yasuharu ;

Takita, Junko ;

Takeuchi, Kengo ;

Niwa, Akira ;

Chen, Yuyan ;

Nakazaki, Kumi ;

Nomoto, Junko ;

Asakura, Yoshitaka ;

Muto, Satsuki ;

Tamura, Azusa ;

Iio, Mitsuru ;

Akatsuka, Yoshiki ;

Hayashi, Yasuhide ;

Mori, Hiraku ;

Igarashi, Takashi ;

Kurokawa, Mineo ;

Chiba, Shigeru ;

Mori, Shigeo ;

Ishikawa, Yuichi ;

Okamoto, Koji ;

Tobinai, Kensei ;

Nakagama, Hitoshi ;

Nakahata, Tatsutoshi ;

Yoshino, Tadashi ;

Kobayashi, Yukio ;

Ogawa, Seishi .

NATURE, 2009, 459 (7247) :712-U118

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